No Evidence for Chronic Demyelination in Spared Axons after Spinal Cord Injury in a Mouse

Abstract

The pattern of remyelination after traumatic spinal cord injury remains elusive, with animal and human studies reporting partial to complete demyelination followed by incomplete remyelination. In the present study, we found that spared rubrospinal tract (RST) axons of passage traced with actively transported dextrans and examined caudally to the lesion 12 weeks after mouse spinal cord contusion injury were fully remyelinated. Spared axons exhibited a marginally reduced myelin thickness and significantly shorter internodes. CASPR (contactin-associated protein) and K v 1.2 channels were used to identify internodes and paranodal protein distribution properties were used as an index of myelin integrity. This is the first time the CNS myelin internode length was measured in a mouse. To better understand the significance of shortened internodes and thinner myelin in spared axons, we modeled conduction properties using McIntyre's et al. model of myelinated axons. Mathematical modeling predicted a 21% decrease in the conduction velocity of remyelinated RST axons attributable to shortened internodes. To determine whether demyelination could be present on axons exhibiting a pathological transport system, we used the retroviral reporter system. Virally delivered green fluorescent protein unveiled a small population of dystrophic RST axons that persist chronically with evident demyelination or abnormal remyelination. Collectively, these data show that lasting demyelination in spared axons is rare and that remyelination of axons of passage occurs in the chronically injured mouse spinal cord.

Remyelination reporter reveals prolonged refinement of spontaneously regenerated myelin

“…Tissues were prepared as described previously (28). Briefly, three injured mice were killed and perfused at 3 MPV with ice-cold 3% (wt/vol) paraformaldehyde/0.5% glutaraldehyde.…”

“…In short, we cannot be sure that all abnormally thin or short myelin is regenerated, nor that all sheaths with normal dimensions are a product of development rather than regeneration. Myelin sheath dimensions affect signal conduction speed considerably, and sluggish conduction following insult has been attributed in part to irregular remyelination (11,12,(26)(27)(28)(29). A better comprehension of these fundamentals is essential in guiding a new understanding of spontaneous myelin regeneration and therapeutic approaches to demyelinating disorders.…”

“…To follow the evolution and maturation of regenerating myelin membranes, we used a model of spinal cord contusion injury known to cause significant partial demyelination of spared axons followed by spontaneous remyelination (28). We targeted reporter expression to the membranes of proliferating NG2 + glial progenitors via postinjury retrovirus injections in a mouse strain that ubiquitously expresses membrane-bound GFP following Cre recombination (30).…”

Glia Disease and Repair—Remyelination

“…When demyelination is induced by toxins injurious to oligodendrocytes and myelin (e.g., by dietary cuprizone or direct delivery of lysolecithin or ethidium bromide), the remyelination usually proceeds to completion, albeit in an age-dependent manner (Blakemore and Franklin 2008). Similarly, there is evidence that axons undergoing primary demyelination in experimental or clinical traumatic injury undergo complete remyelination, and that the persistence of chronically demyelinated axons is unusual (Lasiene et al 2008). An exception is when demyelination is induced by, or associated with, the adaptive immune response, such as occurs in the autoimmune-mediated condition multiple sclerosis (MS) and its laboratory animal model, experimental autoimmune encephalomyelitis (EAE).…”

Functional implications of demyelination and the molecular control of remyelination in the adult mouse.

“…In animal models, chronic demyelination has been described (Gledhill et al, 1973;Blakemore, 1974;Gledhill and McDonald, 1977;Blight, 1983;Totoiu and Keirstead, 2005) while little chronic demyelination is reported in humans (Gensert and Goldman, 1997;Kakulas, 1999;Guest et al, 2005). However, recent evidence has suggested that remyelination is far more extensive in animal models when accounting for which axons remain spared and traverse the lesion (Lasiene et al, 2008).…”